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A New Look at the Functional Organization of the Golgi Ribbon

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A New Look at the Functional Organization of the Golgi Ribbon

Jaakko Saraste et al. Front Cell Dev Biol.

Abstract

A characteristic feature of vertebrate cells is a Golgi ribbon consisting of multiple cisternal stacks connected into a single-copy organelle next to the centrosome. Despite numerous studies, the mechanisms that link the stacks together and the functional significance of ribbon formation remain poorly understood. Nevertheless, these questions are of considerable interest, since there is increasing evidence that Golgi fragmentation - the unlinking of the stacks in the ribbon - is intimately connected not only to normal physiological processes, such as cell division and migration, but also to pathological states, including neurodegeneration and cancer. Challenging a commonly held view that ribbon architecture involves the formation of homotypic tubular bridges between the Golgi stacks, we present an alternative model, based on direct interaction between the biosynthetic (pre-Golgi) and endocytic (post-Golgi) membrane networks and their connection with the centrosome. We propose that the central domains of these permanent pre- and post-Golgi networks function together in the biogenesis and maintenance of the more transient Golgi stacks, and thereby establish "linker compartments" that dynamically join the stacks together. This model provides insight into the reversible fragmentation of the Golgi ribbon that takes place in dividing and migrating cells and its regulation along a cell surface - Golgi - centrosome axis. Moreover, it helps to understand transport pathways that either traverse or bypass the Golgi stacks and the positioning of the Golgi apparatus in differentiated neuronal, epithelial, and muscle cells.

Keywords: Golgi bypass; Golgi ribbon; cell differentiation; cell migration; centrosome; intermediate compartment; mitosis; recycling endosome.

Figures

FIGURE 1
FIGURE 1
Building blocks of the Golgi apparatus. A model suggesting modular assembly and disassembly of the Golgi apparatus, based on its organization in various cell types and during different stages of the cell cycle. The prevailing view is that the preformed Golgi stacks in mammalian cells extend tubules that undergo tethering and fusion, thereby giving rise to a continuous Golgi ribbon consisting of compact (stacked) and non-compact (tubular) regions. Here, we argue that the non-compact zones are structurally more complex, being occupied by pleiomorphic “linker compartments”, which due to their function in the biogenesis of the Golgi stacks also dynamically join them together.
FIGURE 2
FIGURE 2
Separation of the linker compartments from the Golgi ribbon provides a landmark for the onset of mitosis and cell motility. At interphase the linker compartments, indicated with a single color (green) reside at the non-compact regions of the Golgi ribbon. (A) At late G2, the repositioning of the duplicated centrosomes is accompanied by the detachment of the linker compartments from the Golgi ribbon and their movement to the cell center along the radial array of centrosome-nucleated MTs (orange). As cells enter mitosis, the pericentrosomal compartments – BRC and ERC – expand and divide as the centrosomes mature, separate and move to form the spindle poles. At prometaphase, when the nuclear membrane breaks down, disassembly of the Golgi stacks (blue) gives rise to a vesicular “Golgi haze”, which together with the permanent compartments at the spindle poles contributes to the reassembly of the Golgi ribbon as cells exit mitosis (not shown). (B) The repolarization of the Golgi apparatus in motile cells is initiated by similar detachment of the linker compartments during the fragmentation of the Golgi ribbon. In this case, however, the joint reorientation of these compartments with the centrosome sets the stage for simultaneous reformation of the stacks and the Golgi ribbon on the other side of the nucleus facing the cell’s leading edge.
FIGURE 3
FIGURE 3
IC elements and REs persist and co-localize during mitosis. Normal rat kidney (NRK) cells stably expressing green fluorescent protein (GFP)-coupled Rab1 as a marker for the IC were labeled with fluorescent transferrin during a 1 h uptake to visualize the endosomal recycling system. At the same time, the cells were exposed to BFA, which disassembles the Golgi stacks, but does not affect mitotic entry or progression. Note the co-localization of the IC elements and REs at the spindle poles of a cell that has reached prometaphase (open arrows), as well as in the pericentrosomal area of interphase cells (arrows) and. In addition, co-localization of the two markers is observed at peripheral sites (arrowheads). The interphase nuclei and mitotic chromosomes are stained with DAPI. Bar = 5 μm (see also Marie et al., 2012; Takatsu et al., 2013).
FIGURE 4
FIGURE 4
Signaling and trafficking along a cell periphery – Golgi – centrosome axis. The proposed joint operation of the IC elements (dark green) and REs (light green) as linker compartments in the Golgi ribbon sets the stage for MT-dependent pathways that connect the cell periphery with the Golgi and the centrosome at the cell center. Besides providing a possible axis for cell signaling this direct connection opens up for transport pathways that bypass the Golgi stacks. Furthermore, the existence of a direct link between IC elements and the cell periphery (Sannerud et al., 2006) raises the possibility that the IC elements and endosomes also meet at ERES. For simplicity, a structure consisting of five stacks displaying uniform cis-trans polarity is shown, while in reality the Golgi ribbon is a twisted, basket-shaped structure in the perinuclear area of a fibroblastic cell. The blow-up illustrates a non-compact region of the Golgi ribbon. The linker compartments derived from the central domains of biosynthetic (IC) and endocytic (EN) networks are schematically depicted as separate structures, although they are expected to establish tubular and saccular continuities between the neighboring stacks (blue). The centrosomal and non-centrosomal (Golgi-nucleated) MTs with plus-minus polarity are indicated in orange and brown color, respectively.
FIGURE 5
FIGURE 5
Role of the biosynthetic and endocytic networks in the organization of endomembranes and Golgi positioning in differentiated cell types. In all cells the centrosomal (or centrosome-derived) and non-centrosomal (Golgi-nucleated) MTs with plus-minus polarity are indicated by orange and brown color, respectively. The IC elements (dark green) and REs (light green) are also depicted by different colors. (A) Highly schematic model of a neuron with its cell body, axon and dendritic tree. Golgi stacks (blue) are present in the cell body (Golgi ribbon) and in the proximal branchpoints of the dendritic tree (Golgi outposts), but are lacking from axons. By contrast, in addition to being present in the cell body, IC elements and REs are found throughout the neuronal periphery. The blow-up highlights synapses with local secretory ERES-IC-RE units. Whether axons contain similar structures is presently unclear. (B) Schematic diagram of a small portion of a long multinucleated skeletal muscle cell. In a terminally differentiated myofiber small Golgi outposts are found in the nuclear periphery and – together with ERES – at specific sites within the myofibrillar system. These sites, which function in the nucleation of longitudinal and vertical bundles of non-centrosomal (Golgi-nucleated) MTs most likely contain also IC elements and REs. (C) In a polarized epithelial cell the tight junctions divide the PM into apical and basolateral domains. The apical PM further consists of ciliary and non-ciliary subdomains. In epithelial cells, as in neurons and muscle cells, the centrosome loses its major role as MT-organizing center and (in this case) forms a basal body at the base of the primary cilium. This function is taken over by sub-apical nucleation sites which, however, remain enigmatic. These sites generate a vertical array of MTs typical for the polarized epithelial cell. The apical region may also contain a lateral array of MTs of mixed polarity (not shown). Moreover, a sub-population of non-centrosomal MTs are nucleated by the Golgi apparatus and grow apically. Rab11-containing apical recycling endosomes (AREs) pile-up at the minus ends of the vertical MTs. Similarly as in the pericentrosomal region of a fibroblastic cell (see Figure 4), a pool of IC elements are proposed join the REs at this location. This conclusion is supported by the existence of a circular membrane compartment at the base of the primary cilium, which is known to contain Rab11 and the IC/cis-Golgi protein GM130.

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